The Ontogeny of Mucosal and Systemic Antibody Responses to HIV-1 Infection

The humoral immune system plays a critical role in the clearance of numerous pathogens. In the setting of HIV-1 infection, the virus infects, integrates its genome into the host's cells, replicates, and establishes a reservoir of virus-infected cells. The initial antibody response to HIV-1 infection is targeted to non-neutralizing epitopes on HIV-1 Env gp41, and when a neutralizing response does develop months after transmission, it is specific for the autologous founder virus and the virus escapes rapidly. After continuous waves of antibody mediated neutralization and viral escape, a small subset of infected individuals eventually develop broad and potent heterologous neutralizing antibodies years after infection. In this dissertation, I have studied the ontogeny of mucosal and systemic antibody responses to HIV-1 infection by means of three distinct aims: 1. Determine the origin of the initial antibody response to HIV-1 infection. 2. Characterize the role of restricted VH and VL gene segment usage in shaping the antibody response to HIV-1 infection. 3. Determine the role of persistence of B cell clonal lineages in shaping the mutation frequencies of HIV-1 reactive antibodies.

After the introduction (Chapter 1) and methods (Chapter 2), Chapter 3 of this dissertation describes a study of the antibody response of terminal ileum B cells to HIV-1 envelope (Env) in early and chronic HIV-1 infection and provides evidence for the role of environmental antigens in shaping the repertoire of B cells that respond to HIV-1 infection. Previous work by Liao et al. demonstrated that the initial plasma cell response in the blood to acute HIV-1 infection is to gp41 and is derived from a polyreactive memory B cell pool. Many of these antibodies cross-reacted with commensal bacteria, Therefore, in Chapter 3, the relationship of intestinal B cell reactivity with commensal bacteria to HIV-1 infection-induced antibody response was probed using single B cell sorting, reverse transcription and nested polymerase chain reaction (RT- PCR) methods, and recombinant antibody technology. The dominant B cell response in the terminal ileum was to HIV-1 envelope (Env) gp41, and 82% of gp41- reactive antibodies cross-reacted with commensal bacteria whole cell lysates. Pyrosequencing of blood B cells revealed HIV-1 antibody clonal lineages shared between ileum and blood. Mutated IgG antibodies cross-reactive with both Env gp41 and commensal bacteria could also be isolated from the terminal ileum of HIV-1 uninfected individuals. Thus, the antibody response to HIV-1 can be shaped by intestinal B cells stimulated by commensal bacteria prior to HIV-1 infection to develop a pre-infection pool of memory B cells cross-reactive with HIV-1 gp41.

Chapter 4 details the study of restricted VH and VL gene segment usage for gp41 and gp120 antibody induction following acute HIV-1 infection; mutations in gp41 lead to virus enhanced neutralization sensitivity. The B cell repertoire of antibodies induced in a HIV-1 infected African individual, CAP206, who developed broadly neutralizing antibodies (bnAbs) directed to the HIV-1 envelope gp41 membrane proximal external region (MPER), is characterized. Understanding the selection of virus mutants by neutralizing antibodies is critical to understanding the role of antibodies in control of HIV-1 replication and prevention from HIV-1 infection. Previously, an MPER neutralizing antibody, CAP206-CH12, with the binding footprint identical to that of MPER broadly neutralizing antibody 4E10, that like 4E10 utilized the VH1-69 and VK3-20 variable gene segments was isolated from this individual (Morris et al., 2011). Using single B cell sorting, RT- PCR methods, and recombinant antibody technology, Chapter 4 describes the isolation of a VH1-69, Vk3-20 glycan-dependent clonal lineage from CAP206, targeted to gp120, that has the property of neutralizing a neutralization sensitive CAP206 transmitted/founder (T/F) and heterologous viruses with mutations at amino acids 680 or 681 in the MPER 4E10/CH12 binding site. These data demonstrate sites within the MPER bnAb epitope (aa 680-681) in which mutations can be selected that lead to viruses with enhanced sensitivity to autologous and heterologous neutralizing antibodies.

In Chapter 5, I have completed a comparison of evolution of B cell clonal lineages in two HIV-1 infected individuals who have a predominant VH1-69 response to HIV-1 infection--one who produces broadly neutralizing MPER-reactive mAbs and one who does not. Autologous neutralization in the plasma takes ~12 weeks to develop (Gray et al., 2007; Tomaras et al., 2008b). Only a small subset of HIV-1 infected individuals develops high plasma levels of broad and potent heterologous neutralization, and when it does occur, it typically takes 3-4 years to develop (Euler et al., 2010; Gray et al., 2007; 2011; Tomaras et al., 2011). The HIV-1 bnAbs that have been isolated to date have a number of unusual characteristics including, autoreactivity and high levels of somatic hypermutations, which are typically tightly regulated by immune control mechanisms (Haynes et al., 2005; 2012b; Kwong and Mascola, 2012; Scheid et al., 2009a). The VH mutation frequencies of bnAbs average ~15% but have been shown to be as high as 32% (reviewed in Mascola and Haynes, 2013; Kwong and Mascola, 2012). The high frequency of somatic hypermutations suggests that the B cell clonal lineages that eventually produce bnAbs undergo high-levels of affinity maturation, implying prolonged germinal center (GC) reactions and high levels of T cell help. To study the duration of HIV-1- reactive B cell clonal persistence, HIV-1 reactive and non HIV-1- reactive B cell clonal lineages were isolated from an HIV-1 infected individual that produces bnAbs, CAP206, and an HIV-1 infected individual who does not produce bnAbs, 004-0. Single B cell sorting, RT-PCR and recombinant antibody technology was used to isolate and produce monoclonal antibodies from multiple time points from each individual. B cell sequences clonally related to mAbs isolated by single cell PCR were identified within pyrosequences of longitudinal samples of these two individuals. Both individuals produced long-lived B cell clones that persisted from 0-232 weeks in CAP206, and 0-238 weeks in 004-0. The average length of persistence of clones containing members isolated from two separate time points was 91.5 weeks both individuals. Examples of the continued evolution of clonal lineages were observed in both the bnAb and non-bnAb individual. These data indicated that the ability to generate persistent and evolving B cell clonal lineages occurs in both bnAb and non-bnAb individuals, suggesting that some alternative host or viral factor is critical for the generation of highly mutated broadly neutralizing antibodies.

Together the studies described in Chapter 3-5 show that multiple factors influence the antibody response to HIV-1 infection. The initial antibody response to HIV-1 Env gp41 can be shaped by a B cell response to intestinal commensal bacteria prior to HIV-1 infection. VH and VL gene segment restriction can impact the B cell response to multiple HIV-1 antigens, and virus escape mutations in the MPER can confer enhanced neutralization sensitivity to autologous and heterologous antibodies. Finally, the ability to generate long-lived HIV-1 clonal lineages in and of itself does not confer on the host the ability to produce bnAbs.

Two Antarctic penguin genomes reveal insights into their evolutionary history and molecular changes related to the Antarctic environment.

BACKGROUND: Penguins are flightless aquatic birds widely distributed in the Southern Hemisphere. The distinctive morphological and physiological features of penguins allow them to live an aquatic life, and some of them have successfully adapted to the hostile environments in Antarctica. To study the phylogenetic and population history of penguins and the molecular basis of their adaptations to Antarctica, we sequenced the genomes of the two Antarctic dwelling penguin species, the Adélie penguin [Pygoscelis adeliae] and emperor penguin [Aptenodytes forsteri]. RESULTS: Phylogenetic dating suggests that early penguins arose ~60 million years ago, coinciding with a period of global warming. Analysis of effective population sizes reveals that the two penguin species experienced population expansions from ~1 million years ago to ~100 thousand years ago, but responded differently to the climatic cooling of the last glacial period. Comparative genomic analyses with other available avian genomes identified molecular changes in genes related to epidermal structure, phototransduction, lipid metabolism, and forelimb morphology. CONCLUSIONS: Our sequencing and initial analyses of the first two penguin genomes provide insights into the timing of penguin origin, fluctuations in effective population sizes of the two penguin species over the past 10 million years, and the potential associations between these biological patterns and global climate change. The molecular changes compared with other avian genomes reflect both shared and diverse adaptations of the two penguin species to the Antarctic environment.

The Frequency and Impact of Exposure to Potentially Traumatic Events Over the Life Course.

We examined the frequency and impact of exposure to potentially traumatic events among a nonclinical sample of older adults (n = 3,575), a population typically underrepresented in epidemiological research concerning the prevalence of traumatic events. Current PTSD symptom severity and the centrality of events to identity were assessed for events nominated as currently most distressing. Approximately 90% of participants experienced one or more potentially traumatic events. Events that occurred with greater frequency early in the life course were associated with more severe PTSD symptoms compared to events that occurred with greater frequency during later decades. Early life traumas, however, were not more central to identity. Results underscore the differential impact of traumatic events experienced throughout the life course. We conclude with suggestions for further research concerning mechanisms that promote the persistence of post-traumatic stress related to early life traumas and empirical evaluation of psychotherapeutic treatments for older adults with PTSD.

SOLO AND CHAMBER CLARINET WORKS BY AMERICAN- BORN WOMEN COMPOSERS: 1990-2005

During the period of 1990-2005, American-born women composers have contributed significantly to the standard clarinet repertoire. Pioneering composers such as Joan Tower, Margaret Brouwer, and Libby Larsen have created staples for clarinet literature. Yet, there is very little scholarly research on women composers of clarinet music, most being concentrated on Joan Tower. Through my research, I have discovered over seventy-five works by more than fifty composers in the following genres: solo clarinet; clarinet and piano; clarinet and voice, with or without piano; and small chamber pieces for up to five players. This performance dissertation project consists of three recitals featuring solo and chamber works by nine living women composers, and program notes containing pertinent biographical and compositional information. My intent is to increase recognition women composers, both prominent and lesser known, who are writing high-quality, accessible clarinet literature. Each woman selected is making a full or partial living from the sales of her compositions, has received recognition through awards, commissions, grants, and frequent performances, and has composed works that are both performer and audience accessible. Recital 1: Trios for Clarinet, Violin, and Piano Commissioned by the Verdehr Trio and Composed by American-Born Women Composers. Composers: Jennifer Higdon, Joan Tower, Margaret Brouwer, and Libby Larsen. Recital II: Programmatic Clarinet Works by American-Born Women Composers. Composers: Andrea Clearfield, Stella Sung, and Karen Amrhein. Recital III: Works for Solo Clarinet, Clarinet and Piano, and Clarinet Concerto Genres by American-Born Women Composers. Composers: Persis Parshall Vehar, Jenni Brandon, Margaret Brouwer, and Libby Larsen.

SELECTED ACCOMPANIED AND UNACCOMPANIED FLUTE WORKS OF RIVIER, BOZZA, AND FRANCAIX

A great deal of flute music written during the twentieth century was the product of French composers for French flutists. Through the course of the century some composers and compositions made it into the standard repertory while the flute works of Rivier, Bozza, and Francaix remained on the periphery. (The composers are listed and discussed chronologically based on date of birth rather than alphabetically.) This dissertation focuses on the accompanied and unaccompanied flute works of these men. It seeks to bring to light works that are almost totally unknown, and places them in relation to the works that have made it into the secondary repertory. The pieces chosen for this project represent each period of the composers' output in relation to the flute works. This dissertation follows the stylistic and technical traits found in the flute works of each composer and, when appropriate, compares the traits among the composers. The following is a list of the works performed: Rivier's Oiseaux tendres, Sonatine, Concerto, Ballade, Virevoltes, Trois Silhouettes, Comme une tendre berceuse . ..; Bozza's Image, Aria, Divertissement op. 39, Soir dans les montagnes, Trois Impressions, Concertina da camera, Cinq Chansons sur des themes Japonais, Phorbeia; Francaix's Divertimento, Concerto, Suite, and Sonate. The written part of this performance dissertation includes biographical information on each composer, program notes for each piece performed, a discography, and a selected bibliography.

[BSHM meetings] Topics in the history of financial mathematics: early commerce to chaos in modern stock markets

This account provides an overview of the study day, entitled 'Topics in the History of Financial Mathematics: Early commerce to chaos in modern stock markets,' held by the British Society for the History of Mathematics jointly with Gresham College, at Gresham College, London on 25th April 2008. The series of talks explored the development of mathematics and mathematical techniques in a commercial and financial context.

Melancholy and the Early Modern University

Critics have observed that in early Stuart England, the broad, socially significant concept of melancholy was recoded as a specifically medical phenomenon—a disease rather than a fashion. This recoding made melancholy seem less a social attitude than a private ailment. However, I argue that at the Stuart universities, this recoded melancholy became a covert expression of the disillusionment, disappointment, and frustration produced by pressures there—the overcrowding and competition which left many men “disappointed” in preferment, alongside James I’s unprecedented royal involvement in the universities. My argument has implications for Jürgen Habermas’s account of the emergence of the public sphere, which he claims did not occur until the eighteenth-century. I argue that although the university was increasingly subordinated to the crown’s authority, a lingering sense of autonomy persisted there, a residue of the medieval university’s relative autonomy from the crown; politicized by the encroaching Stuart presence, an alienated community at the university formed a kind of public in private from authority within that authority’s midst. The audience for the printed book, a sphere apart from court or university, represented a forum in which the publicity at the universities could be consolidated, especially in seemingly “private” literary forms such as the treatise on melancholy. I argue that Robert Burton’s exaggerated performance of melancholy in The Anatomy of Melancholy, which gains him license to say almost anything, resembles the performed melancholy that the student-prince Hamlet uses to frustrate his uncle’s attempts to surveil him. After tracing melancholy’s evolving literary function through Hamlet, I go on to discuss James’s interventions into the universities. I conclude by considering two printed (and widely circulated) books by university men: the aforementioned The Anatomy of Melancholy by Burton, an Oxford cleric, and The Temple by George Herbert, who left a career as Cambridge’s public orator to become a country parson. I examine how each of these books uses the affective pattern of courtly-scholarly disappointment—transumed by Burton as melancholy, and by Herbert as holy affliction—to develop an empathic form of publicity among its readership which is in tacit opposition to the Stuart court.

Description and search labor for information retrieval

Selection power is taken as the fundamental value for information retrieval systems. Selection power is regarded as produced by selection labor, which itself separates historically into description and search labor. As forms of mental labor, description and search labor participate in the conditions for labor and for mental labor. Concepts and distinctions applicable to physical and mental labor are indicated, introducing the necessity of labor for survival, the idea of technology as a human construction, and the possibility of the transfer of human labor to technology. Distinctions specific to mental labor, particular between semantic and syntactic labor, are introduced. Description labor is exemplified by cataloging, classification, and database description, can be more formally understood as the labor involved in the transformation of objects for description into searchable descriptions, and is also understood to include interpretation. The costs of description labor are discussed. Search labor is conceived as the labor expended in searching systems. For both description and search labor, there has been a progressive reduction in direct human labor, with its syntactic aspects transferred to technology, effectively compelled by the high relative costs of direct human labor compared to machine processes.

Distance and Proximity in Service to the Empire: Ulster and New Zealand between the Wars

This essay uses the concepts of ‘distance’ and ‘proximity’ to investigate and assess perceptions of community, nation and empire in inter-war New Zealand and Ulster (as well as Ireland and Northern Ireland) within a British imperial context, and explores the extent to which service of the empire (for example in the First World War) promoted both notions of imperial unity and local autonomy. It focuses on how these perceptions were articulated in the inter-war years during visits to Northern Ireland by three New Zealand premiers – Massey, Forbes and Coates – and to New Zealand by the Prime Minister of Northern Ireland, Lord Craigavon. It discusses the significant ways in which distance from their ‘home base’ and proximity to expatriate communities (in Craigavon's case) and Irish unionists and nationalists (in the case of the New Zealand premiers) inflected public statements during their visits. By examining these inter-war visits and investigating the rhetoric used and the cultural demonstrations associated with them, the factors of both distance and proximity can be used to evaluate similarities and difference across two parts of the empire. Thus, we can throw some light on the nature and dynamics of British imperial identity in the early twentieth century.

Bax and the 'Celtic North'

A feature of scholarship on Arnold Bax is his indebtedness, in his early works, to the Irish literary revival (particularly in the mythology-suffused works of 'AE' and early Yeats) and, in his later works, to the music of Jean Sibelius, and the relationship between these periods. I argue that this relationship, which I summarize by using Bax's portmanteau term of 'Celtic North', is underpinned by the stimulus of landscape, which, as well as being a means by which to return to the Romantic idea of the sublime, also provides a means by which Bax critiques the more modernist relationship with landscape that underpins the English pastoral school of the 1920s. Thus the 'Celtic North' is the antithesis to the English 'south land' of Vaughan Williams and others.

Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants

Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N=211 infants (n=137 born preterm 32 weeks gestational age [GA] and n=74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.

'Big, strong and healthy'. Young children's identification of food and drink that contribute to healthy growth

Growing awareness of the importance of healthy diet in early childhood makes it important to chart the development of children's understanding of food and drink. This study aimed to document young children's evaluation of food and drink as healthy, and to explore relationships with socioeconomic status, family eating habits, and children's television viewing. Data were gathered from children aged 3-5. years (. n=. 172) in diverse socioeconomic settings in Ireland, and from their parents. Results demonstrated that children had very high levels of ability to identify healthy foods as important for growth and health, but considerably less ability to reject unhealthy items, although knowledge of these increased significantly between ages 3 and 5. Awareness of which foods were healthy, and which foods were not, was not related to family socioeconomic status, parent or child home eating habits, or children's television viewing. Results highlighted the importance of examining young children's response patterns, as many of the youngest showed a consistent 'yes bias'; however, after excluding these responses, the significant findings remained. Findings suggest it is important to teach children about less healthy foods in the preschool years. © 2013 Elsevier Ltd.

Institutional Frameworks and Structural Factors Relating to Educational Access Across Europe

In this article institutional and structural factors relating to access to education are assessed. First, the macro frameworks of institutional regulation that exert influence on the educational trajectories of young Europeans are demonstrated. Based on different aspects of these frameworks and drawing from extant research, the article presents a typology of education systems that provide varying levels of access to and accessibility of education in Finland, France, Germany, Italy, Poland, the Netherlands, Slovenia, and the United Kingdom. Second, using survey data (N = 6,366) it analyzes the impact of gender and parental education on young people’s educational aspirations and early labor-market entry across the countries.